If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
Synonyms: norepinephrine and epinephrine degradation
|Superclasses:||Degradation/Utilization/Assimilation → Hormones Degradation|
Expected Taxonomic Range:
The catecholamines dopamine, (R)-noradrenaline (norepinephrine), and (R)-adrenaline (epinephrine) function as neurotransmitters and hormones. They have important physiological regulatory roles and are involved in the development of many diseases. Their biosynthesis from L-tyrosine is shown in pathway catecholamine biosynthesis. Overall, approximately half of the dopamine produced in the body is not converted to (R)-noradrenaline and is degraded to inactive metabolites (in [Eisenhofer97]) (see pathway dopamine degradation). Although the degradation of endogenous catecholamines has been well studied, many inaccuracies based on early studies still remain in the literature. For example, (R)-noradrenaline degradation has been depicted as a series of reactions, including oxidative deamination, that form 3,4-dihydroxymandelate, followed by O-methylation to form vanillyl mandelate. However, updated pathways are shown in [Eisenhofer04] and here.
Catecholamines are biosynthesized in both neuronal and non-neuronal cells, including the central nervous system, sympathetic nerves, adrenal medulla, gastrointestinal tract, and kidneys. They have previously been considered to be metabolized after their release from cells. They are now believed to be largely metabolized in the cells in which they are biosynthesized. In addition, intracellular catecholamines stored in vesicles were believed to be released extracellularly only upon stimulation. It is now thought that vesicular catecholamines are in a dynamic equilibrium with the cytoplasm. Outward leakage from vesicles is countered by active transport back into vesicles by monoamine transporters. The small amount of catecholamines remaining in the cytoplasm are a major source of metabolites. Reviewed in [Eisenhofer04].
The metabolism of the transient (and toxic) aldehyde intermediates of catecholamine metabolism 3,4-dihydroxyphenylglycolaldehyde (this pathway) and 3,4-dihydroxyphenylacetaldehyde (see pathway dopamine degradation) is dependent upon the presence (in (R)-noradrenaline and (R)-adrenaline) or absence (in dopamine) of the β-hydroxyl group. Its absence in dopamine and 3,4-dihydroxyphenylacetaldehyde favors oxidation by aldehyde dehydrogenase. Its presence in (R)-noradrenaline, (R)-adrenaline and 3,4-dihydroxyphenylglycolaldehyde favors reduction by aldehyde reductase, or aldose reductase. Thus, dopamine is preferentially converted to an acid metabolite, and (R)-noradrenaline and (R)-adrenaline are preferentially converted to an alcohol metabolite. Reviewed in [Eisenhofer04].
About This Pathway
The major route of vanillyl mandelate production from (R)-noradrenaline and (R)-adrenaline is currently believed to involve initial oxidative deamination to the unstable aldehyde intermediate 3,4-dihydroxyphenylglycolaldehyde and reduction to 3,4-dihydroxyphenylglycol by aldehyde reductase (alcohol dehydrogenase) [Mardh86] (or aldose reductase as stated in [Eisenhofer04]). These reactions occur mainly in neuronal tissue, whereas the O-methylation of (R)-noradrenaline and 3,4-dihydroxyphenylglycol occurs in extraneuronal tissues. 3,4-dihydroxyphenylglycol is O-methylated to 3-methoxy-4-hydroxyphenylglycol and this alcohol is dehydrogenated to the unstable aldehyde intermediate 3-methoxy-4-hydroxyphenylglycolaldehyde which is then dehydrogenated to vanillyl mandelate, the major end product of (R)-noradrenaline and (R)-adrenaline degradation. Alcohol dehydrogenase and aldehyde dehydrogenase play the major role in vanillyl mandelate production in liver. vanillyl mandelate is excreted in urine. Reviewed in [Eisenhofer04, Goldstein03].
An alternative route following the oxidative deamination of (R)-noradrenaline and (R)-adrenaline to 3,4-dihydroxyphenylacetaldehyde is its dehydrogenation to 3,4-dihydroxymandelate, which was believed for many years to be the main route. It is now considered by [Eisenhofer04] to be quantitatively insignificant under normal conditions and 3,4-dihydroxyphenylglycol is the main product (see above). Consequently, the O-methylation of 3,4-dihydroxymandelate to vanillyl mandelate is no longer considered to be the main source of vanillyl mandelate. Reviewed in [Eisenhofer04].
Two minor routes that contribute to vanillyl mandelate production are via the O-methylation of (R)-noradrenaline and (R)-adrenaline to normetanephrine and metanephrine, respectively. These compounds are oxidatively deaminated to the unstable aldehyde intermediate 3-methoxy-4-hydroxyphenylglycolaldehyde [Suzuki85]. This compound may also be reduced to 3-methoxy-4-hydroxyphenylglycol in a minor reverse reaction. Reviewed in [Eisenhofer04].
In addition to the above pathways, the sulfates of normetanephrine, metanephrine and 3-methoxy-4-hydroxyphenylglycol can be formed by sulfotransferase 1A3/1A4 (EC 22.214.171.124) in cells that contain this activity. Glucuronides of these compounds may also be formed and are either excreted in bile, or they may enter the circulation and be excreted in urine (reviewed in [Goldstein03]) (not shown).
Relationship Links: KEGG:PART-OF:map00350
Eisenhofer97: Eisenhofer G, Aneman A, Friberg P, Hooper D, Fandriks L, Lonroth H, Hunyady B, Mezey E (1997). "Substantial production of dopamine in the human gastrointestinal tract." J Clin Endocrinol Metab 82(11);3864-71. PMID: 9360553
Mardh86: Mardh G, Dingley AL, Auld DS, Vallee BL (1986). "Human class II (pi) alcohol dehydrogenase has a redox-specific function in norepinephrine metabolism." Proc Natl Acad Sci U S A 83(23);8908-12. PMID: 3466164
Ashibe07: Ashibe B, Hirai T, Higashi K, Sekimizu K, Motojima K (2007). "Dual subcellular localization in the endoplasmic reticulum and peroxisomes and a vital role in protecting against oxidative stress of fatty aldehyde dehydrogenase are achieved by alternative splicing." J Biol Chem 282(28);20763-73. PMID: 17510064
Baetge88: Baetge EE, Behringer RR, Messing A, Brinster RL, Palmiter RD (1988). "Transgenic mice express the human phenylethanolamine N-methyltransferase gene in adrenal medulla and retina." Proc Natl Acad Sci U S A 85(10);3648-52. PMID: 2835776
Bai07: Bai HW, Shim JY, Yu J, Zhu BT (2007). "Biochemical and molecular modeling studies of the O-methylation of various endogenous and exogenous catechol substrates catalyzed by recombinant human soluble and membrane-bound catechol-O-methyltransferases." Chem Res Toxicol 20(10);1409-25. PMID: 17880176
Begun02: Begun J, McLeish MJ, Caine JM, Palant E, Grunewald GL, Martin JL (2002). "Crystallization of PNMT, the adrenaline-synthesizing enzyme, is critically dependent on a high protein concentration." Acta Crystallogr D Biol Crystallogr 58(Pt 2);314-5. PMID: 11807261
Bertocci91: Bertocci B, Miggiano V, Da Prada M, Dembic Z, Lahm HW, Malherbe P (1991). "Human catechol-O-methyltransferase: cloning and expression of the membrane-associated form." Proc Natl Acad Sci U S A 88(4);1416-20. PMID: 1847521
Boleda93: Boleda MD, Saubi N, Farres J, Pares X (1993). "Physiological substrates for rat alcohol dehydrogenase classes: aldehydes of lipid peroxidation, omega-hydroxyfatty acids, and retinoids." Arch Biochem Biophys 307(1);85-90. PMID: 8239669
Bonifacio01: Bonifacio MJ, Vieira-Coelho MA, Soares-da-Silva P (2001). "Expression and characterization of rat soluble catechol-O-methyltransferase fusion protein." Protein Expr Purif 23(1);106-12. PMID: 11570851
Braun87: Braun T, Bober E, Singh S, Agarwal DP, Goedde HW (1987). "Evidence for a signal peptide at the amino-terminal end of human mitochondrial aldehyde dehydrogenase." FEBS Lett 215(2);233-6. PMID: 3582651
Burnell87: Burnell JC, Carr LG, Dwulet FE, Edenberg HJ, Li TK, Bosron WF (1987). "The human beta 3 alcohol dehydrogenase subunit differs from beta 1 by a Cys for Arg-369 substitution which decreases NAD(H) binding." Biochem Biophys Res Commun 146(3);1127-33. PMID: 3619918
Chrostek03: Chrostek L, Jelski W, Szmitkowski M, Puchalski Z (2003). "Gender-related differences in hepatic activity of alcohol dehydrogenase isoenzymes and aldehyde dehydrogenase in humans." J Clin Lab Anal 17(3);93-6. PMID: 12696080
Chrostek03a: Chrostek L, Jelski W, Szmitkowski M, Puchalski Z (2003). "Alcohol dehydrogenase (ADH) isoenzymes and aldehyde dehydrogenase (ALDH) activity in the human pancreas." Dig Dis Sci 48(7);1230-3. PMID: 12870777
Showing only 20 references. To show more, press the button "Show all references".
©2015 SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025-3493